Impact of tamoxifen treatment on neutrophils in breast cancer patients

Project Summary Tamoxifen (TMX) is a selective estrogen receptor modulator (SERM) approved by FDA for treatment of estrogen receptor positive (ER+) early stage and advanced breast cancer. Although TMX is the mainstay of breast cancer treatment, 20-30% of of breast cancer patients exhibit an existing or developing resistance to TMX therapy with cancer metastsis, by poorly understood mechanisms. Therefore an understanding of molecular mechanisms and predictive correlates of these pathological effects associated with TMX treatment will help design improved adjuvant therapies to overcome TMX resistance and related pathologies for effective management of breast cancer. In this regard, we recently reported that TMX induces robust formation of neutrophil extracellular traps (NETs), which are DNA fibrils exuded from activated neutrophils that can trap and kill extracellular pathogens to boost antimicrobial host defense in chronic granulomatous disease. However, unconstrained NET release has been linked to several immunopathologies including cancer. Because breast cancer patients are typically prescribed TMX as the first or second line therapy, we hypothesize that long-term TMX treatment induces NET formation in these patients, which correlates with and can account for TMX resistance and cancer metastasis. This hypothesis is supported by our preliminary data showing that the extent of NET formation in breast cancer patients is directly proportional to the duration of TMX treatment and that NETs purified from TMX treated breast cancer patients increase cancer cell survival. Leveraging a characterized large cohort of breast cancer patients treated with TMX at MD Anderson Cancer Center, in this clinical exploratory study we will quantify and characterize NETs in blood samples from pre- and post- menopausal women diagnosed with ERα+ breast cancer receiving TMX therapy for varying durations of time, and correlate it with clinical data on co-morbidities, cancer metastasis and recurrence (Aim 1a). We will examine the phenotype and transcriptional landscape of neutrophils from these patients with a focus on TMX-activated NET pathway dentified by us (Aim 1b). Lastly, we will determine the direct impact of TMX-induced NETs on survival and transcriptional reprogramming of breast cancer cells in response to tamoxifen exposure (Aim 2). Because the NET-inducing action of TMX in breast cancer patients and its impact on breast cancer cells as it relates to tamoxifen resistance is completely unknown, our proposed studies will provide novel insights into the mechanism of tamoxifen resistance and future therapeutic opportunities to prevent cancer metastasis and other adverse effects of TMX.